The present invention relates to 5,11-dihydrodibenzo [b,e][1,4]oxazepine derivatives antagonistic to calcium channel and useful for treating or preventing abnormal motor functions of gastrointestinal tracts, particularly intestinal diseases such as irritable bowel syndrome, stereoisomers thereof, pharmacologically acceptable salts thereof or hydrates thereof, and pharmaceutical compositions containing them as active ingredients.
It is disclosed in, for example, European Patent No. 0404359A1 that 5,11-dihydrodibenzo[b,e][1,4]thiazepine derivatives are usable as calcium channel antagonists selectively effective on gastrointestinal tracts. Quinn, P. et al., Brit. J. Pharmacol. 1994, 112 (Suppl.), Abst 573P and Wallis R. M. et al. Brit. J. Pharmacol. 1994, 112 (Suppl.), Abst. 574P disclose that (S)-5-[[1-(4-methoxyphenyl)ethyl]pyrrolidine-2-ylmethyl]-5,11-dihydrodibenzo[b,e][1,4]thiazepine maleate which is one of derivatives of those compounds has effects similar to the effects of them. Further, International Patent No. 9733885A1 discloses 5-(2-pyrrolidinyl-methyl)-5,11-dihydrodibenzo [b,e][1,4]oxazepine derivatives as medicines for improving motor insufficiency of gastrointestinal tracts. However, the activity and selectivity of these compounds toward gastrointestinal tracts are yet insufficient, and another defect of them is that they have an anticholinergic effect which causes side effects such as thirstiness and mydriasis.
As social environments have been complicated recently, many of people feel the severe stress and patients with irritative bowel syndrome having cardinal symptoms of irregular bowel movement and abdominal pain are increasing in number. Medicines used for improving these diseases are, for example, cholinergic blocking agents, laxatives, antidiarrheal agents, intestinal drugs, mucosal paralyzers, gastrointestinal function regulators, autonomic nerve regulators, Chinese medicines, anxiolytic agents, antidepressant agents, sleep promoting drugs and neurotropic agents. However, the clinical effects of these medicines are yet insufficient and, in addition, they are not always satisfactory from the viewpoint of side effects of them. Under these circumstances, the development of medicines of a new type for improving the gastrointestinal function regulators, which have no side effect, is demanded.
The object of the present invention is to provide new compounds having an excellent effect of improving the gastrointestinal function.
Another object of the present invention is to provide a pharmaceutical composition containing the new compound.
Calcium channel antagonists having an effect of inhibiting the smooth muscle contraction are effective against diseases caused by an abnormal acceleration of contraction of intestinal tracts such as intestinal diseases, e.g. irritative bowel syndrome. In fact, it was reported that calcium channel antagonists such as nicardipine and verapamil are effective against irritative bowel syndrome [Am. J. Gastroenterol., 80, 317 (1985), Gut, 28, 1609 (1987), J. Clin. Psychiatry, 48, 388 (1987) and Pharmacol. Ther., 60, 121 (1993)]. However, the calcium channel antagonists are scarcely used for the clinical treatment because of the main effect of them on the cardiovascular system. Under these circumstances, the inventors made intensive investigations on the development of calcium channel antagonists selective to the intestinal tracts but having only a low toxicity or in other words, ineffective on cardiovascular system for the purpose of obtaining therapeutic agents for intestinal diseases such as abnormal motor functions of gastrointestinal tracts, particularly irritable bowel syndrome. After the investigations, the inventors have found that compounds represented by following general formula [Ia], [Ib] or [Ic] have calcium channel antagonistic activity selective to the intestinal tracts and, therefore, they are effective as agents for regulating gastrointestinal function. The present invention has been completed on the basis of this finding. These compounds have excellent pharmacological effects and, in addition, they are highly soluble in water. It is expected, therefore, that when they are orally administered, they are rapidly absorbed well. It is also expected that when they are used in the form of a liquid preparation, the production of the preparation is easy.
Namely, the present invention relates to 5,11-dihydrodibenzo[b,e][1,4]oxazepine derivatives of following general formula [Ia], [Ib] or [Ic], stereoisomers thereof, pharmacologically acceptable salts thereof or hydrates thereof, and pharmaceutical compositions containing them as active ingredients: 
wherein R1 to R5 may be the same or different from each other and they each represent hydrogen atom, a halogen atom, cyano group, hydroxyl group, a lower alkyl group, a lower alkoxyl group, amino group or a lower alkylamino group, or R1 and R2, R2 and R3, R3 and R4 or R4 and R5 together represent xe2x80x94O(CH2)nOxe2x80x94 group (n being 1, 2 or 3), R6 represents hydrogen or a lower alkyl group, Y represents methylene group, oxygen atom, sulfur atom or an alkylamino group, A represents CH2, CHOH, CO or O, B represents CH2, CHOH or CO, or A-B represents CHxe2x95x90CH, and D represents CH2, CH2xe2x80x94CH2 or CH2xe2x80x94CH2xe2x80x94CH2, or B-D represents CH2.
In R1 to R5 in [Ia], [Ib] and [Ic] in the general formula, the halogen atoms include fluorine atom, chlorine atom, etc., the lower alkyl groups include those having 1 to 5 carbon atoms such as methyl group, ethyl group and n-propyl group, the lower alkoxyl groups include those having 1 to 5 carbon atoms such as methoxyl, ethoxyl and n-propoxyl group, the lower alkylamino groups include monoalkylamino groups and dialkylamino groups, and xe2x80x94O(CH2)nOxe2x80x94 groups include methylenedioxy group, ethylenedioxy group and propylenedioxy group. Among them, the halogen atoms are preferably fluorine atom and chlorine atom, and the lower alkyl groups are preferably those having 1 to 3 carbon atoms. The lower alkoxyl groups are preferably those having 1 to 3 carbon atoms. The monoalkylamino groups and dialkylamino groups are preferably those wherein the alkyl groups have 1 to 5 carbon atoms, more preferably those wherein the alkyl groups have 1 to 3 carbon atoms.
A-B-D is preferably any of CH2xe2x80x94CH2, COxe2x80x94CH2, CHOHxe2x80x94CH2, CHOHxe2x80x94CH2xe2x80x94CH2, CH2xe2x80x94CHOHxe2x80x94CH2, CHxe2x95x90CHxe2x80x94CH2, COxe2x80x94CH2xe2x80x94CH2, Oxe2x80x94CH2xe2x80x94CH2, CH2xe2x80x94COxe2x80x94CH2 or CH2xe2x80x94CH2xe2x80x94CH2.
In general formula [Ia] in the present invention, Y is preferably methylene group and R1 to R5 are not hydrogen atoms at the same time. In the present invention, one of R1 to R5 is preferably amino group or a lower alkylamino group and the others are hydrogen atom, or R2 or R3 is a halogen atom, a lower alkyl group or a lower alkoxyl group. It is also preferred that either R2 or R3 or both of R2 and R3 are methoxyl group, or R2 and R3 together form methylenedioxy group, and R1, R4 and R5 are hydrogen atom. It is further preferred that R3 is methoxyl group, and R1, R2, R3, R4 and R5 are each hydrogen atom, Y is methylene group, and A and B-D are CH2. When Y is methylene group, preferably the absolute configuration at the 2-position of the piperidine ring is R-configuration, and when Y is not methylene group, the position thereof in the nitrogen-containing 6-membered ring has a configuration similar to it. In those compounds, examples of particularly preferred compounds are (R)-5,11-dihydro-5-[1-(4-methoxyphenethyl)piperidine-2-ylmethyl]dibenzo [b,e][1,4] oxazepine (Ia-1), (R)-5,11-dihydro-5-[1-(4-dimethylaminophenethyl) piperidine-2-ylmethyl]dibenzo[b,e][1,4]oxazepine (Ia-2), (R)-5,11-dihydro-5-[1-(3-methoxyphenethyl)piperidine-2-ylmethyl]dibenzo [b,e][1,4]oxazepine, (R)-5,11-dihydro-5-[1-[3-(4-methoxyphenyl)propyl]piperidine-2-ylmethyl]dibenzo[b,e][1,4]oxazepine, (R)-5,11-dihydro-5-[1-(3,4-methylenedioxyphenethyl)piperidine-2-ylmethyl]dibenzo[b,e][1,4] oxazepine and (R)-5-[1-(4-chlorophenethyl)piperidine-2-ylmethyl]-5,11-dihydrodibenzo[b,e][1,4]oxazepine, represented by the following formulae, and pharmacologically acceptable salts and hydrates of them. 
In general formula [Ib], it is preferred in the present invention that R1 to R5 are not hydrogen atoms at the same time. In the present invention, one of R1 to R5 is preferably amino group or a lower alkylamino group and the others are hydrogen atom, or R2 or R3 is a halogen atom, a lower alkyl group or a lower alkoxyl group. It is also preferred that either R2 or R3 or both of R2 and R3 are methoxyl group, or R2 and R3 together form methylenedioxy group, and R1, R4 and R5 are each hydrogen atom. It is further preferred that R3 is methoxyl group, and R1, R2, R4 and R5 are each hydrogen atom. A and B-D both represent CH2. It is also preferred that the absolute configuration at the 3-position of the pyrrolidine ring is R-configuration. In those compounds, examples of particularly preferred compounds are (R)-5,11-dihydro-5-[1-(4-methoxyphenethyl)pyrrolidine-3-yl]dibenzo[b,e][1,4]oxazepine (Ib-1), (R)-5,11-dihydro-5-[1-(4-dimethylaminophenethyl)pyrrolidine-3-yl]dibenzo [b,e][1,4]oxazepine (Ib-2), (R)-5,11-dihydro-5-[1-[3-(4-methoxyphenyl) propyl]pyrrolidine-3-yl]dibenzo[b,e][1,4]oxazepine, (R)-5,11-dihydro-5-[1-(3,4-methylenedioxyphenethyl)pyrrolidine-3-yl]dibenzo[b,e][1,4]oxazepine and (R)-5-[1-(4-chlorophenethyl)pyrrolidine-3-yl]-5,11-dihydro-dibenzo[b,e][1,4]oxazepine, represented by the following formulae, and pharmacologically acceptable salts and hydrates of them. 
In general formula [Ic], it is preferred in the present invention that R6 is a lower alkyl group having 1 to 3 carbon atoms. Preferably, R1 to R5 are not hydrogen atoms at the same time. In the present invention, one of R1 to R5 is preferably amino group or a lower alkylamino group and the others are each hydrogen atom, or R2 or R3 is a halogen atom, a lower alkyl group or a lower alkoxyl group. It is also preferred that either R2 or R3 or both of R2 and R3 are methoxyl group, or R2 and R3 together form methylenedioxy group, and R1, R4 and R5 are hydrogen atom. It is further preferred that R3 is methoxyl group, and R1, R2, R4 and R5 are each hydrogen atom. R6 is preferably a lower alkyl group having 1 to 3 carbon atoms. In those compounds, examples of particularly preferred compounds are 5,11-dihydro-5-[2-[N-(4-methoxyphenethyl)-N-methyl-amino]ethyl]dibenzo[b,e][1,4]oxazepine (Ic-1), 5,11-dihydro-5-[2-[N-(3-methoxyphenethyl)-N-methylamino]ethyl]dibenzo[b,e][1,4]oxazepine (Ic-2), 5,11-dihydro-5-[2-[N-[3-(4-methoxyphenyl)propyl]-N-methylamino]ethyl]dibenzo[b,e][1,4]oxazepine (Ic-3), 5,11-dihydro-5-[2-[N-methyl-N-(3,4-methylenedioxyphenethyl)amino]ethyl]dibenzo[b,e][1,4]oxazepine (Ic-4), 5-[2-[N-(4-chlorophenethyl)-N-methylamino]ethyl]-5,11-dihydro-dibenzo[b,e][1,4]oxazepine, 5,11-dihydro-5-[2-[N-(4-dimethylamino-phenethyl)-N-methylamino]ethyl]dibenzo[b,e][1,4]oxazepine (Ic-5) and 5,11-dihydro-5-[2-[N-(3-dimethylaminophenethyl)-N-methylamino]ethyl]dibenzo[b,e][1,4]oxazepine represented by the following formulae, and pharmacologically acceptable salts and hydrates of them. 
The pharmacologically acceptable salts of the compounds of the present invention are, for example, salts with mineral acids (inorganic acids) such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and salts with organic acids such as acetic acid, lactic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, oxalic acid, aspartic acid and methanesulfonic acid. In those salts, the inorganic salts are preferred.
Compounds [Ia] and [Ib] of the present invention have one or more asymmetric carbon atoms and, therefore, there can be optical isomers of them. The optical isomers, mixtures of them and racemic compounds are included in the compounds of the present invention. In those compounds, the configuration at the 2-position of the piperidine ring is preferably R-configuration, and when Y is not methylene group, the configuration is preferably similar to it. The compounds of the present invention and pharmacologically acceptable salts thereof may be in the form of hydrates or solvates thereof. These hydrates or solvates are also included in the present invention.
Compounds [Ia] of the present invention can be produced by, for example, following process A: 
wherein R1 to R5, A, B, D and Y are as defined above, and X represents chlorine atom, bromine atom or iodine atom.
Compounds [Ia] of the present invention can be produced by reacting a compound [IIa] with a halide represented by above general formula [IIIa] in the presence of a base in a solvent.
The reaction solvents suitable for the above-described reaction are dimethyl sulfoxide; amides such as N,N-dimethylformamide; ethers such as tetrahydrofuran, diethyl ether, dioxane and 1,2-dimethoxyethane; acetonitrile; toluene; xylene; benzene and the like. The bases are, for example, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, lithium diisopropylamide, n-butyl lithium, sodium methoxide and potassium t-butoxide.
The reaction temperature is usually 0 to 150xc2x0 C., preferably in the range of room temperature to 100xc2x0 C. The reaction time, which varies depending on the reaction temperature and the variety of the solvent, is usually 1 to 50 hours.
The amounts of compound [IIIa] and the base are 0.5 to 5 molar equivalents, preferably 0.8 to 2 molar equivalents, per molar equivalent of the compound [IIa].
Compounds [IIa] used as the starting material for the above-described reaction can be produced by a publicly known method [J. Med. Chem., 7, 609 (1964)].
The halides of above general formula [IIIa] can be produced by reducing pipecolic acid, 3-morpholinecarboxylic acid or the like to obtain an amino alcohol, N-alkylating the amino alcohol and halogenating the alcohol moiety of the resulting compound with mesyl chloride, tosyl chloride or the like. The ring is enlarged by this process.
Compounds [Ia] of the present invention can be produced by following process B: 
wherein R1 to R5, A, B, D and Y are as defined above, V represents a protective group for amino group such as t-butoxycarbonyl group, benzyloxycarbonyl group or tosyl group, and W and Wxe2x80x2 each represent a leaving group such as chlorine atom, bromine atom, iodine atom, mesyloxy group or tosyloxy group.
Compounds [Ia] of the present invention can be produced by dropping N-t-butoxycarbonyl-2-piperidylmethyl tosylate of above general formula [IVa] or the like into compound [IIa] in the presence of a base to conduct the reaction and thereby obtaining a compound of general formula [Va], then removing the protective group to obtain a compound of general formula [VIa] and reacting this compound with a compound of general formula [VIIa] in the presence of a base. The solvents and bases used for the reactions for obtaining the compound [Va] from compound [IIa], and compound [Ia] from compound [VIa] may be the same as those usable for above-described reaction A.
Compounds [IVa] can be obtained by reducing pipecolic acid, 3-morpholinecarboxylic acid or the like, protecting an amino group of the obtained amino alcohol and converting the alcohol moiety to a leaving group by an ordinary method.
Compounds [Ib] of the present invention can be produced by, for example, the following process: 
wherein R1 to R5, A, B and D are as defined above, and X represents a leaving group such as a halogen atom, tosyloxy group or mesyloxy group.
The solvents suitable for use for the above reaction are dimethyl sulfoxide; amides such as N,N-dimethylformamide, ethers such as tetrahydrofuran, diethyl ether, dioxane and 1,2-dimethoxyethane, acetonitrile, toluene, xylene, benzene and the like. The bases are, for example, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, lithium diisopropylamide, n-butyllithium, sodium methoxide and potassium t-butoxide.
The reaction temperature is usually 0 to 150xc2x0 C., preferably in the range of room temperature to 100xc2x0 C. The reaction time, which varies depending on the reaction temperature and the variety of the solvent, is usually 1 to 50 hours.
The amounts of compound [IIb] and the base are 0.5 to 10 molar equivalents, preferably 0.8 to 5 molar equivalents, per molar equivalent of compound [IIIb].
Compounds [IIb] used as the starting materials for the above-described reaction can be prepared by a publicly known method [J. Med. Chem., 7, 609 (1964)].
Compounds of above general formula [IIIb] can be obtained by N-alkylating 3-hydroxypyrrolidine and then reacting the obtained product with phosphorus oxychloride, thionyl chloride, tosyl chloride, mesyl chloride or the like.
The absolute configuration of pyrrolidine ring varies depending on the absolute structure of 3-hydroxypyrrolidine used as the starting material, and the variety and introduction method of the leaving group. For example, when mesyloxy group or tosyloxy group is used as the leaving group, the steric inversion occurs in the condensation reaction and, therefore, S-compound can be obtained from (R)-3-hydroxypyrrolidine and R-compound can be obtained from (S)-3-hydroxypyrrolidine.
Compounds [Ic] of the present invention can be produced by, for example, the following process: 
wherein R1 to R6, A, B and D are as defined above, and X and Y each represent a leaving group such as a halogen atom, tosyloxy group or mesyloxy group.
Namely, a compound [IIc] is converted to a compound of above general formula [IIIc], which is then reacted with a compound of general formula [IVc] in the presence of a base. The reaction solvents suitable for use for the above reaction are dimethyl sulfoxide, amides such as N,N-dimethylformamide, ethers such as tetrahydrofuran, diethyl ether, dioxane and 1,2-dimethoxyethane, acetonitrile, toluene, xylene, benzene and the like. The bases are, for example, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, lithium diisopropylamide, n-butyllithium, sodium methoxide and potassium t-butoxide.
The reaction temperature is usually 0 to 150xc2x0 C., preferably in the range of room temperature to 100xc2x0 C. The reaction time, which varies depending on the reaction temperature and the variety of the solvent, is usually 1 to 50 hours. The amount of the base is at least equimolar to that of compound [IIIc], preferably 1 to 5 mols per mol of compound [IIIc]. The molar ratio of compound [IIIc] to compound [IVvc] is 0.5/1 to 2/1, preferably 0.7/1 to 1.5/1.
Compounds [Ic] of the present invention can be obtained by converting compound [IIc] to a compound of above general formula [Vc] and condensing the obtained compound with compound [VIc] in the presence of a base. The reaction solvent and base used for the condensation reaction can be the same as those in the above-described reaction. The reaction temperature and the reaction time are also as described above. The amount of the base is at least equimolar to compound [VIc], preferably 1 to 5 mols per mol of compound [VIc]. The molar ratio of compound [Vc] to compound [VIc] is 0.5/1 to 2/1, preferably 0.7/1 to 1.5/1.
Compound [IIc] used as the starting material for the above-described reaction can be prepared by a publicly known method [J. Med. Chem., 7, 609 (1964)]. Compounds [IIIc] can be easily obtained by a combination of known processes. Namely, it can be prepared by alkylating compound [IIc] with a haloacetic ester, reducing the obtained product to obtain an alcohol, converting the hydroxyl group of the alcohol into a leaving group or alkylating compound [IIc] with a 2-haloethanol, in which the hydroxyl group is protected, removing the protective group and converting the hydroxyl group into a leaving group. Compounds [IVc] can be easily obtained by various known methods such as the alkylation reaction of an amine with a corresponding halide, reductive alkylation reaction of an amine with a corresponding aldehyde, and the acylation of an amine with a corresponding carboxylic acid followed by the reduction.
Compounds [Vc] can be easily obtained by various known methods such as the alkylation of compound [IIc] with a haloacetic amide followed by the reduction of the alkylation product, or by the alkylation of compound [IIc] with a haloacetic ester followed by the amidation.
When the compounds of the present invention are used in the form of a pharmaceutical preparation or a pharmaceutical composition, they can be suitably mixed with a pharmaceutically acceptable additive such as an excipient, a carrier or a diluent, and orally or parenterally administered in the form of tablets, capsules, granules, grains, powder, pills, syrup, suspension, emulsion, ointment, suppositories or injection. In the present invention, a pharmaceutical preparation or a pharmaceutical composition containing a compound of the present invention as the active ingredient and a pharmaceutically acceptable carrier and/or diluent is preferred. The carriers and diluents include, for example, glucose, sucrose, lactose, talc, silica, cellulose, methylcellulose, starch, gelatin, ethylene glycol, polyethylene glycol, glycerol, ethanol, water and oils and fats.
The dose and dosage of the compounds of the present invention are suitably variable depending on the variety of the disease, age, body weight, etc. of the patient. For example, when the compounds of the present invention are orally administered for treating intestinal diseases, such as irritable bowel syndrome, about 0.1 to 1,000 mg/day/adult thereof is given at once or in several portions.